cGMP (guanosine-3′,5′-cyclic monophosphate, cyclic GMP) is a cyclic nucleotide, exists in cells of animals and plants, is an intracellular second messenger involved in various cell reactions, and it can be hydrolyzed by PDE-5(phosphodiesterase-5). When PDE-5 is inhibited, the level of cGMP would increase and result in many physiological effects such as vascular smooth muscle diastole. Hence, PDE-5 inhibitors can be used for treatment of diseases caused by cGMP signal transduction disorder, including hypertension, heart failure, pulmonary arterial hypertension, erectile dysfunction, prostatic hyperplasia and female sexual dysfunction, etc.
Erectile dysfunction (ED) is the most common sexual dysfunction in adult males, referring to a disease that penis is continuously unable to achieve or maintain an erection so as to enjoy sexual life. ED includes organic ED, psychological ED and mixed ED. Although ED is not lethal disease, it has a strong impact on life quality and goodwill between spouses.
There are many therapies for treatment of ED, mainly comprising three aspects: peripheral drug therapies, central drug therapies and genetic therapies. Peripheral drug therapies principally refer to applications of phosphodiesterase-5 inhibitors (e.g., sildenafil), as well as applications of papaverine, soluble guanylate cyclase activators, Rho kinase agonists and topical alprostadil. Central drug therapies refer to therapies using drugs such as dopamine receptor agonists, a adrenergic receptor antagonists, 5-hydroxytryptamine (5-HT) receptor agonists, oxytocin and oxytocin receptor agonists. In genetic therapies, on the basis that ion channel is an important material basis for regulating the tension of corpus cavernosum smooth muscle, plasmid vector hMaxi-K (pVAX-hSLO) expressing hSlo gene is injected into corpus cavernosum, which expresses in corpus cavernosum smooth muscle, generates more potassium channels so as to render corpus cavernosum relaxation.
Currently, there are many therapies for treatment of ED, among which phosphodiesterase-5 (PDE-5) inhibitors with sildenafil (Vigra) as representative are first-line drugs for treatment of ED, and are the most popular therapy in patients. At present, PED-5 inhibitors in market include Sildenafil, Vardenafil, Tadalafil, Udenafil and Avanafil, etc. These drugs are taken orally and conveniently, act quickly and have good efficiency. Among them, Sildenafil and Tadalafil are most important profitable products of Pfizer and Eli Lilly Company, respectively. Hence, these drugs have huge market volume.

In patent application WO200119802 (published on 2001 Mar. 22) of Tanabe Seiyaku CO., LTD, the following compounds are disclosed:

In view of epidemiology, many elderly male patients have ED accompanied with other diseases of genitourinary system, such as lower urinary tract symptoms (LUTS) including benign prostatic hyperplasia (BPH), overactive bladder syndrome (OAB), etc. These diseases bring about tremendous distress to the elderly patients and seriously affect their life. The pathological analysis shows ED and LUTS have same pathogenesis, and both of them associate with smooth muscle contraction or smooth muscle cell proliferation. Thus, it is possible to use PDE-5 inhibitor to treat LUTS with same pathogenesis. Tadalafil has been approved by FDA for use in the treatment of benign prostatic hyperplasia.
With the clinical application of PDE-5 inhibitors, some latent safety problems gradually appear. Among the drugs, Sildenafil and Vardenafil not only have inhibition on PDE-5 but also have a certain inhibitory effect on PDE-6, which affects retinal function, so these two drugs may influence human vision, and especially more reports relate to Sildenafil in this aspect. Therefore, these two drugs have poor selectivity on PDE-5. Tadalafil has better selectivity on PDE-6, but still has inhibition effects on PDE-11 in some extent. Although the clinical pharmacological effects of PDE-11 are unknown, there is still latent risk. Some documents report Tadalafil may cause osphyalgia, while more researches are still in need to determine its relevance to PDE-11. In addition, Vardenafil has a low bioavailability and requires an increased dosage of administration, which is disadvantage for long-term medication. The half-life of Tadalafil, as long as about 16 h in human, may readily result in drug interaction if a patient takes other drugs simultaneously, for example, when nitrate drugs and Tadalafil are used together, blood pressure may drop too much in patients, thereby causing life risk.
Avanafil belongs to the second generation of PDE-5 inhibitors, which has good selectivity to PDE-6, with the ration PDE-6/5 of 120. Moreover, it does not inhibit PDE-11, which ensures the safety for clinical treatment. However, this drug has poor enzymatic activity in vitro, its clinical dosage is very high (50 mg, 100 mg and 200 mg), higher than that of Sildenafil, Vardenafil and Tadalafil, which constitutes a safety hazard for clinical treatment in patients. In addition, with the increase of dosage, therapeutic cost increases as well. So Avanafil should be further improved at least in view of pharmacoeconomics. The most common adverse reactions in clinical research reports include headache, flush, nasal congestion, nasopharyngitis or backache. A rare side effect of Avanafil is sudden decrease or loss of eyesight of the men taking this drug. Avanafil has relatively low bioavailability, high clinical dosage, short half-life (as short as about 1.2 h in vivo), so it can only be used for single treatment of erectile dysfunction, and is not suitable for treatment of BPH, OAB and so on. Hence, it is significant to develop PDE-5 inhibitors with high selectivity, more potent pharmacological activity, high bioavailability, higher safety and appropriate (longer but not too much longer) half-life so as to improve life quality (treatment of ED, BPH and LUTS) of elderly patients.
However, most of these compounds have disadvantage of poor water solubility, which brings about difficulty in delivering drug to patients, such as high pill burden. The low water solubility of compounds is disadvantageous to the formation of preparations, cosolvents such as surfactants may have to be used. It results in that the doses of these compounds are strictly restricted in some specific liquid dosage forms, such as the dose of liquid encapsulated in soft gelatin capsules. In order to improve water solubility of these compounds, the drug load per unit dose for the compounds may have to be increased, which brings about serious side-effects on human body. In addition, high pill burden would further increase the daily dosage of patients, which may impair compliance of patients, and thus the optimal therapeutic effects of medication may not be achieved. Moreover, the poor solubility of these compounds means potential possibility of crystallization and precipitation from solution under storage and/or transportation conditions, which may cause safety problems of drugs in clinical implications.
In summary, it is now a hotspot of research to find compounds inhibiting PDE-5, especially with good activity, high selectivity and capable of solving poor solubility of these compounds, to effectively overcome difficulties of preparing various preparations such as oral, intravenous injection and intramuscular injection preparations, and to broaden clinical application.